1-Department of Pediatric Medicine-Division of Endocrinology, St. Jude Children s Research

Transcription

1 Page 1 of 43 Accepted Preprint first posted on 2 February 2017 as Manuscript EJE Title: Endocrine Late-Effects of Childhood Cancer and its Treatments Authors: Wassim Chemaitilly, MD 1, 2 and Laurie E. Cohen, MD 3, 4 Affiliations: 1-Department of Pediatric Medicine-Division of Endocrinology, St. Jude Children s Research Hospital, Memphis, Tennessee, United States of America. 2-Department of Epidemiology and Cancer Control, St. Jude Children s Research Hospital, Memphis, Tennessee, United States of America. 3-Division of Endocrinology, Boston Children s Hospital; Harvard Medical School, Boston, Massachusetts, United States of America. 4-Dana-Farber -Boston Children s Hospital Center for Cancer and Blood Disorders, Cancer Survivorship Program, Boston, Massachusetts, United States of America. Corresponding Author: Wassim Chemaitilly, MD St. Jude Children s Research Hospital Division of Endocrinology 262 Danny Thomas Place MS 737, Memphis TN38105 Phone Fax wassim.chemaitilly@stjude.org Short Title: Endocrine Late Effects of Childhood Cancer Keywords: Childhood Cancer Survivor, Endocrine Late-Effects, Endocrine Complications, Radiotherapy Late-Effects, Chemotherapy Late-Effects. Word Count: 5960 Tables/Figures: 3 Tables, 1 Figure 1 Copyright 2017 European Society of Endocrinology.

2 Page 2 of Abstract Endocrine complications are frequently observed in childhood cancer survivors (CCS). One of two CCS will experience at least one endocrine complication during the course of his / her lifespan, most commonly as a late-effect of cancer treatments, especially radiotherapy and alkylating agent chemotherapy. Endocrine late-effects include impairments of the hypothalamus / pituitary, thyroid, and gonads, as well as decreased bone mineral density and metabolic derangements leading to obesity and/or diabetes mellitus. A systematic approach where CCS are screened for endocrine late-effects based on their cancer history and treatment exposures may improve health outcomes by allowing the early diagnosis and treatment of these complications. 33 2

3 Page 3 of Introduction Childhood cancer cure rates have substantially improved over the past five decades, resulting in a growing number of long-term survivors. In the USA, it is estimated that one out of 530 adults in their second or third decade of life is a childhood cancer survivor (CCS) 1. Progress in this field is owed to treatments incorporating chemotherapy and / or radiotherapy in conjunction with supportive care to address acute complications. Surviving patients may go on to experience late-onset chronic health conditions months to decades after the primary cancer; such conditions are described as late-effects 2. Endocrine complications are among the most common late-effects in CCS and they frequently occur because of exposures to radiotherapy and / or alkylating agent chemotherapy. It is estimated that 50% of CCS will experience at least one endocrine or reproductive complication during the course of her or his lifetime 3. The present manuscript offers a summary of the main endocrine late-effects in CCS including hypothalamic/pituitary (HP) axis dysfunction and complications affecting the thyroid and gonads, as well as decreased bone mineral density (BMD) and metabolic derangements leading to obesity and/or diabetes mellitus HP Axis Dysfunction HP axis dysfunction includes the following disorders: growth hormone (GH) deficiency (GHD), central precocious puberty (CPP), luteinizing hormone (LH) / follicle stimulating hormone (FSH) deficiency (LH/FSHD), thyroid stimulating hormone (TSH) deficiency (TSHD), adrenocorticotropic hormone (ACTH) deficiency (ACTHD), hyperprolactinemia, and central diabetes insipidus. HP axis dysfunction is frequently observed in survivors of central nervous system (CNS) tumors and those whose HP region was exposed to radiation 4. Data supporting 3

4 Page 4 of associations between conventional chemotherapy and irreversible HP axis dysfunction are limited 5-7. Novel targeted chemotherapy agents such as tyrosine kinase inhibitors (TKI) 8, 9 and immune system modulators 10 seem to be associated with HP disorders. The presentation of HP axis dysfunction varies according to tumor location and treatment modalities. Patients experiencing direct HP injury related to local tumor growth or surgical resection generally present with multiple and simultaneously occurring HP disorders at the time of tumor diagnosis or shortly after surgery. In contrast, patients with radiation-induced dysfunction are diagnosed with one or multiple HP disorders often sequentially and over a period of time extending from a few months to several decades 4, 11, 12. Central diabetes insipidus, a common and challenging complication of tumors or surgical resections involving the HP region, does not occur as a late-effect; it will therefore not be discussed in the present summary 4. The risk of radiation-related HP axis dysfunction increases with the dose of radiation and the duration of follow-up 12. In a study of 748 adult CCS exposed to cranial radiotherapy (CRT) and followed for a mean 27.3 years, the prevalence of having one HP disorder was 51.4% and that of having more than one disorder approached 11% (Figure 1) 12. Changes in the delivery of radiation, such as the use of proton radiotherapy, may modify the risk or the latency period for the onset of HP axis dysfunction Similarly, the mechanisms and lasting impact of novel targeted chemotherapy agents have yet to be fully elucidated 8, 10. Information on the screening and management of HP disorders is summarized in Table GHD Prevalence and Risk Factors 4

5 Page 5 of GHD is the most common, and often only, HP disorder observed in survivors of CNS tumors and those whose HP region was exposed to radiotherapy 11, 12. With a prevalence of 12.5%, GHD is the most common endocrine disorder in childhood CNS survivors even after the exclusion of patients with HP tumors 4. The prevalence is even higher in patients exposed to high dose CRT; for example, the cumulative incidence of GHD exceeded 90% at 4 years of follow-up after the treatment of medulloblastoma 11. The highest risk factors include tumor growth or surgery within or near the HP region, and HP radiation doses 18 Gy 4, 12, 16. Patients exposed to Gy may also develop GHD if followed for an extended period of time as the risk increases in a both dose and time-dependent fashion 17. Patients with HP exposure to radiotherapy for other reasons than CNS tumors, such as acute lymphoblastic leukemia (ALL) with CNS involvement requiring CRT or historic cases where this was done prophylactically 18-20, diseases requiring hematopoietic stem-cell transplant (HSCT) after conditioning with total body irradiation (TBI) or non-brain solid tumors of the head such as retinoblastoma 28, 29, nasopharyngeal carcinoma 30 or soft-tissue / rhabdomyosarcoma 31 of the head are all at risk of developing GHD as a late-effect. Young age at exposure to radiotherapy is an additional risk factor 12, 20, 32. GHD has been described in a small number of patients treated with conventional chemotherapy alone 5-7 and may also occur following treatment with targeted chemotherapy agents. Children treated for chronic myelogenous leukemia with imatinib mesylate, a TKI, may experience linear growth deceleration or arrest, but whether this side-effect is related to GHD, resistance to GH, or direct skeletal toxicity remains unclear 9, 33, 34. Ipilimumab, an anti-ctla4 monoclonal antibody that is increasingly used to treat unresectable melanoma has been associated with hypophysitis and GHD, possibly persisting after the discontinuation of therapy 10. 5

6 Page 6 of Diagnosis and Management GH deficient children and adolescents usually present with decreased linear growth velocity with sex- and age-adjusted values < -2 SD over one year or <-1.5 SD over 2 years. Patients with untreated GHD eventually develop short stature (height < -2SD) and medical providers should ideally not wait for this advanced stage to initiate referrals or investigations 35. Growth failure is frequently multifactorial in CCS and may involve the direct effects on the growth plates of certain therapies such as retinoic acid for the treatment of neuroblastoma 36, nutritional causes and other chronic illnesses. Particular attention should be paid to body proportions and pubertal stage as these can confound or delay the diagnosis of GHD. Vertebral growth plate damage from spinal radiotherapy and complications related to spinal surgery and / or scoliosis can affect the growth of the spine more severely than that of the extremities; the impact of these situations on a patient s stature can be assessed by measuring and monitoring the sitting height (or upper to lower segment ratio) 37. Patients who experience GHD and CPP simultaneously may maintain over a period of time a seemingly normal linear growth velocity due to sex steroids increasing GH secretion and inducing local growth factors in the bone Because of rapid fusion of the growth plates under the action of sex steroids, this situation can potentially cause irreversible losses in final height if both conditions are not rapidly detected and treated 41. Linear growth, GH secretion and skeletal maturation may also be influenced by obesity 42. The diagnosis of GHD in CCS requires a good understanding of the limitations of laboratory testing modalities in this population. Insulin-like growth factor (IGF)-1 and IGFbinding protein 3 (IGFBP-3) levels may not be accurate surrogate markers in CCS 43, 44. While failing one stimulation test (and not two as in the general population) is felt to be enough for the 6

7 Page 7 of diagnosis in CCS with tumors or radiation involving the HP region due to high pre-test probability 35, GH stimulation tests may not always be reliable 45. GH releasing hormone should not be used for dynamic testing in CCS treated with CRT given the risk of a falsely negative result due to the likely hypothalamic origin of GHD in this population Skeletal maturation should be assessed using a bone age X-ray 50. Replacement with human recombinant GH (hgh) allows CCS to improve their height prospects, but patients may not entirely recover their adult height potential (based on pretreatment height prediction or mid-parental height) because of other factors such as skeletal / spinal sequelae, abnormal pubertal timing, chronic illness, and primary disease burden 21, 24, Pro-mitogenic and proliferative in-vitro properties of GH and IGF-1 have raised concerns regarding the safety of hgh in CCS 55, 56. Long-term follow-up data do not support increased risks of mortality or cancer recurrence in CCS treated with hgh 57, 58. Treatment with hgh was associated with a higher risk of second neoplasms, mostly meningioma (itself a known complication of CRT), in two reports from a large multi-center Childhood Cancer Survivor Study (CCSS) 57, 58. These findings were not replicated by studies from other cohorts 59 or by a more recent report from the CCSS focusing on second CNS neoplasms 60. Treatment with hgh is generally offered one year after the completion of cancer treatments in GH deficient children in the absence of active neoplasia 56. There are no specific guidelines regarding the observation time needed in children treated for non-malignant CNS tumors such as craniopharyngioma 56. Over the past two decades, the use of hgh has been extended to GH deficient adults given possible benefits on lipids, bone mass, body composition, and quality of life 61, 62. However, there are no studies demonstrating a lasting benefit of treating GHD specifically in adult CCS

8 Page 8 of CPP Prevalence and Risk Factors CPP is defined by the onset of pubertal development as a result of the premature activation of the HP-gonadal axis before the ages of 8 or 9 years in girls and boys, respectively 63, 64. Children with tumors located near the hypothalamus and optic pathways such as low grade gliomas (with or without neurofibromatosis type 1), and with HP exposure to radiotherapy at doses Gy are at risk of developing CPP 54, 65, 66. CPP has also been reported, albeit less frequently, in children treated with CRT for acute leukemia, non-brain solid tumors of the head 32, 54 and in survivors treated with TBI for HSCT 67. The prevalence of CPP in CNS tumor survivors has been reported at % 4, 54 and is even higher in patients with tumors located in the HP region (26-29%) 54, 65. Hydrocephalus 4, 65, 66, young age at CNS radiation (< 5 years) 68, 69, female sex, and increased BMI 68 are additional risk factors. Diagnosis and Management The diagnostic approach to CPP in CCS is similar to that used in the general population 64, 70. Clinicians should nevertheless be aware of certain features that are specific to CCS 71. Testicular volume may not accurately reflect the pubertal stage of boys treated with gonadotoxic modalities (high dose alkylating agents or direct testicular radiotherapy) (Table 3); treatmentinduced germ cell and Sertoli cell injury may result in small testicular size without impairing 166 testosterone secretion in these patients Scrotal thinning, penile length and pubarche supplemented by AM testosterone and LH plasma levels may be more reliable indicators 71. The frequent occurrence of CPP and GHD within the same time frame and the possible association with other endocrine late-effects are additional challenges 71. The treatment of CPP in CCS primarily relies on gonadotropin releasing hormone agonist depot preparations 70. Patients with a history of CPP may experience LH/FSHD as a late-effect of CNS radiotherapy several years later 8

9 Page 9 of and, paradoxically, require long-term sex-hormone replacement therapy 54. Tumor burden and co-morbidities may impair a patient s ability to fully recover her/ his pre-treatment growth potential: a mean final height loss of 0.9 SD was reported in patients with a history of CPP within a cohort of prospectively assessed CCS LH/FSHD Prevalence and Risk Factors Patients with LH/FSHD experience a deficiency in sex-hormone secretion because of insufficient stimulation from the hypothalamus and/ or the pituitary. The prevalence in CCS was recently reported at 6.5% overall 75 and 11% among those exposed to CRT 12. The main risk factors are tumor growth, surgery, and radiation at doses 30 Gy affecting the HP region 12, 49. LH/FSHD could also occur as a late-effect of HP irradiation at lower doses with longer followup 12. It has also been reported in patients treated with TBI 75 as well as those treated with radiotherapy for non-brain solid tumors of the head 30, 32, 76. Hypophysitis subsequent to the use of ipilimumab may also result in LH/FSHD 10. Diagnosis and Management Depending on attained pubertal stage at the time of onset of LH/FSHD, CCS may present with pubertal delay, arrested puberty, primary or secondary amenorrhea, or sex hormone deprivation symptoms. The diagnosis and management of LH/FSHD in CCS follow the same steps as in the general population. The laboratory diagnosis is based on measurement of LH, FSH and estradiol (females) or AM testosterone (males) 77, 78. The treatment of LH/FSHD in CCS relies on sex-hormone replacement therapy

10 Page 10 of TSHD Prevalence and Risk Factors The prevalence of TSHD has been reported at % in survivors of CNS tumors and those treated with CRT 12. The main risk factors are tumor growth, surgery, or radiation at doses 30 Gy affecting the HP region 4, 12. TSHD could also occur as a late-effect of HP irradiation at lower doses with longer follow-up 12. Hidden forms of TSHD have been described in HSCT recipients conditioned with TBI 82. The clinical relevance of the subtle laboratory findings upon which these diagnoses were based is questionable 83. TSHD has also been described in a small number of patients treated with radiotherapy for retinoblastoma and other non-brain solid tumors of the head 29, 32, 76. Hypophysitis subsequent to the use of ipilimumab may also result in TSHD 10. Diagnosis and Management Patients with TSHD may experience symptoms of hypothyroidism. The laboratory diagnosis is based on the observation of plasma free T4 (FT4) levels below the normal range coinciding with TSH levels that are either low or inappropriately normal 77. The treatment relies on replacement with levothyroxine and follows the same steps as in the general population 77. In contrast to the more common primary hypothyroidism, the adjustment of thyroid replacement in patients with TSHD cannot be guided by TSH levels. Given that CCS with TSHD are frequently at risk of developing other HP axis dysfunctions, screening and treatment for ACTHD should precede thyroid replacement: treatment of hypothyroidism can precipitate patients with undiagnosed adrenal insufficiency into adrenal crisis ACTHD Prevalence and Risk Factors 10

11 Page 11 of Patients with ACTHD, have decreased cortisol secretion because of insufficient HP stimulation. Mineralocorticoid secretion is not significantly impaired in these patients because it is regulated by a different hormonal pathway, the renin-angiotensin-aldosterone system. The prevalence in CCS with a history of CNS tumors or radiotherapy has been reported at 4-5% 4, 12. Tumoral growth, surgery and radiation doses 30 Gy involving the HPA region are the main risk factors 12, 49. ACTHD could also occur as a late-effect of HP irradiation at lower doses with longer follow-up 12, 84. A relatively high incidence (24%) of ACTHD was reported in a study of CCS treated with HSCT, but this was likely over-estimated by the use of testing modalities that are subject to significant variability 85. ACTHD has also been reported in a small number of CCS treated with radiotherapy for non-brain solid tumors of the head 30, 32, 76. Hypophysitis subsequent to the use of ipilimumab may also result in ACTHD 10. Diagnosis and Management Patients with ACTHD may experience symptoms of fatigue, a greater vulnerability to infections and, if untreated during an acute stressor, are at risk of shock and severe complications 77. The potential severity of this complication mandates a high index of suspicion and at-risk patients should be screened at least yearly by the measurement of an 8 AM plasma cortisol level: values < 83 nmol/l (3 micrograms/dl) are suggestive of ACTHD while those > 413 nmol/l (15 micrograms/dl) allow excluding it as a diagnosis 77. Patients with levels nmol/l should ideally receive confirmatory dynamic testing such as the low-dose ACTH stimulation test 77, 86. The treatment relies on maintenance oral doses of hydrocortisone and teaching patients / families how to escalate doses and / or use injectable forms in situations of emergency ( stress dosing ). Patients should carry at all times documentation (cards, bracelets etc.) that can inform emergency personnel of their risk of adrenal crisis. Patients who are also at 11

12 Page 12 of risk of TSHD or primary hypothyroidism should be screened for ACTHD and treated for it before the initiation of thyroid replacement Hyperprolactinemia Hyperprolactinemia may affect up to 30% of childhood CNS tumor survivors treated with high-dose CRT ( Gy, with a mean 53.6 Gy) 49. The main risk factor is radiotherapy at doses 50 Gy. Hyperprolactinemia in CCS is rarely symptomatic given that patients treated with such regimens frequently have primary gonadal late-effects as well 87. Symptomatic CCS can be treated similarly to patients in the general population Thyroid Disorders Thyroid disorders in CCS include primary hypothyroidism, auto-immune thyroid diseases, hyperthyroidism, and thyroid cancer 16. Thyroid complications are among the most common endocrine sequelae in the overall population of CCS 3, 16. The risk of developing primary thyroid disease was significantly higher in survivors than in sibling controls regardless of exposure to high-risk treatments, such as neck radiotherapy, in a recent report from the CCSS 16. Information on the screening and management of thyroid disorders is summarized in Table 2. Primary Hypothyroidism Prevalence and Risk Factors Primary hypothyroidism is one of the most common endocrine late effects reported in CCS 3, 16, 88. Its overall prevalence among adult CCS has been reported at % 3, 89. One of the highest rates is in survivors of pediatric Hodgkin Lymphoma, where up to 50% experienced hypothyroidism at 20 years from diagnosis following thyroid exposure to radiation doses 45 12

13 Page 13 of Gy 88. The prevalence of hypothyroidism in patients treated with HSCT was reported between 14% and 52% Its cumulative incidence among CCS of embryonal tumors of the CNS treated with cranial and craniospinal irradiation was 65±7% by 4 years of follow-up 11. With a prevalence of 10%, primary hypothyroidism is also among the most common endocrine complications reported in survivors of malignant extra-cranial solid tumors 76. The main risk factor of primary hypothyroidism in CCS is the exposure of the thyroid gland to radiation; the risk increases in a both time and dose-dependent fashion 16, 88. Patients with Hodgkin Lymphoma receiving radiation to areas including the thyroid gland (such as mantle fields) represent a high risk group 88. Female sex and longer durations of follow up are additional risk factors 88. In HSCT recipients, the main risk factor is conditioning with TBI, especially when treatment is delivered in a single fraction 91. Conditioning with chemotherapy alone such as with busulfan and cyclophosphamide may be associated with transient and often compensated forms of hypothyroidism 90, 94. The treatment of neuroblastoma with (131) I- metaiodobenzylguanidine ( 131 I-MIBG) is a significant risk factor of primary hypothyroidism, which may occur despite prophylaxis with potassium iodide (KI) 95. Primary hypothyroidism has also been reported in patients treated with radiotherapy for nasopharyngeal carcinoma, retinoblastoma, rhabdomyosarcoma, and other extra-cranial solid tumors of the head and neck 29, 30, 32, 76. Treatment with TKIs such as sorafenib, sunitinib and imatinib has been associated with primary hypothyroidism. Possible mechanisms include inflammation, changes in iodine uptake, or in the capillary vascularization of the thyroid 8, 96. Diagnosis and Management Patients at risk for primary hypothyroidism following exposure to radiotherapy should be screened for this condition at least yearly (more frequently during childhood) by measuring 13

14 Page 14 of plasma levels of FT4 and TSH. Patients on maintenance chemotherapy with TKI should also be screened at regular intervals 8. Treatment with levothyroxine may be justified in compensated states (patients with elevated TSH and normal FT4 plasma levels) in patients with a history of neck irradiation because of the trophic effect of TSH on thyroid epithelial cells and the potential association between chronic TSH elevation and thyroid neoplasia 97. The treatment of compensated forms in patients on TKI remains controversial 8. Plasma levels of TSH should be carefully interpreted in CCS treated for primary hypothyroidism following cranio-spinal radiotherapy. These patients can develop super-imposed TSHD over time and have declining TSH values despite being on adequate doses of replacement; the titration of levothyroxine in this situation should primarily be guided by FT4 levels 77. Patients who are at risk of ACTHD (following cranio-spinal radiotherapy for e.g.) should be screened for this condition and treated with hydrocortisone prior to the initiation of thyroid replacement 77. Autoimmune Thyroid Diseases A small number of patients treated with HSCT were reported to develop auto-immune thyroid disease, most likely because of the transfer of abnormal T or B- lymphocyte clones from the graft donor to the transplant recipient. These patients may require treatment for primary hypothyroidism, or, less frequently, hyperthyroidism 98. Patients on maintenance chemotherapy with immunomodulators such as pegylated interferon and anti-ctla4 monoclonal antibodies (for e.g. ipilimumab or bevacizumab) may also develop auto-immune thyroiditis and require treatment for decompensated primary hypothyroidism 10, 96. Patients treated with HSCT should have measurements of FT4 and TSH at least yearly; those with abnormal function tests should get thyroid antibody measurements in order to elucidate the etiology. Screening by measuring plasma thyroid auto-antibodies, FT4 and TSH levels should be offered to patients treated with 14

15 Page 15 of immunomodulators upon protocol initiation and FT4 and TSH levels should regularly be repeated thereafter 10. Hyperthyroidism Hyperthyroidism has been reported in CNS tumor survivors treated with cranio-spinal radiotherapy, in the context of HSCT-induced auto-immune disease, and in survivors of pediatric Hodgkin Lymphoma with thyroid radiation doses > Gy 16, 88, 98. Management follows a similar approach to that utilized in the general population with the understanding that hyperthyroidism is frequently transient in CCS, and patients may develop primary hypothyroidism subsequently in many instances 98. Thyroid Cancer Prevalence and Risk Factors Thyroid cancer is one of the most common subsequent malignancies experienced by CCS; it is a source of significant concern to survivors whose treatments resulted in thyroid exposure to direct or scatter radiation 16. Thyroid cancer was diagnosed 18.4 times more than expected in survivors of pediatric Hodgkin Lymphoma who were treated with radiotherapy 88. In this population, the risk follows an inverted U-shaped curve; it increases with radiotherapy doses up to Gy and then decreases again at higher doses likely because of the ablation of the thyroid gland 99. Treatment for a primary cancer before 10 years of age 88 and exposure to alkylating agents 100 were additional risk factors. Secondary thyroid cancer has also been reported in survivors of medulloblastoma treated with craniospinal radiotherapy 101, patients conditioned with TBI for HSCT , survivors of ALL treated with CRT 103, , patients treated with 131 I-MIBG for neuroblastoma despite prophylaxis with KI, 109 and those treated with radiotherapy for non-brain solid tumors of the head and neck 32,

16 Page 16 of Diagnosis and Management Screening modalities for thyroid cancer in at-risk CCS are subject to controversy. False positive results from ultrasound studies may trigger anxiety and unnecessary additional procedures 103. Some authors argue that these issues may outweigh the hypothetical benefits of an earlier diagnosis obtained via ultrasound when compared to what can be accomplished through a careful yearly clinical examination of the neck by an experienced provider 103. Others have favored using ultrasound and postulated that it will result in diagnosing the disease at a less advanced stage and hence decrease the need for invasive treatments 111. Expert panels have neither discouraged nor explicitly endorsed screening via ultrasound 112. The diagnosis and management of secondary thyroid cancer in CCS follows the same steps as that of primary thyroid cancer in the general population 112, Primary Testicular Disorders The testes have two distinct functional compartments that show different degrees of vulnerability to cancer treatments; a sex hormone producing compartment comprising the Leydig cells and a reproductive compartment that includes the germ cells and their supporting system (such as the Sertoli cells). While both compartments may be damaged by alkylating agents (Table 3) and radiotherapy, Leydig cells tend to be resilient to these treatments in comparison to the germ cells 81. The result of this differential vulnerability is a commonly observed phenotype in male CCS exposed to high dose chemotherapy, many of whom are able to achieve complete virilization owing to normal Leydig cell function and yet have small testes because of Sertoli cell injury and germ cell depletion; medical care providers should be familiar with this presentation

17 Page 17 of Information on the screening and management of primary testicular disorders is summarized in Table 2. Leydig Cell Failure Prevalence and Risk Factors The prevalence of Leydig cell failure among patients exposed to high risk therapies (alkylating agents or radiation potentially affecting the male reproductive system) has been reported at % in adult CCS followed long-term 3, 89. The prevalence of Leydig cell failure among CCS treated with alkylating agents was reported at 10-57% but it was subclinical in the vast majority of cases (normal testosterone values with elevated LH) and rarely required treatment In contrast, up to 80% of male survivors of ALL treated with radiotherapy for testicular relapse with doses > 20 Gy to the testes have been reported to require treatment with testosterone 117. Leydig cell failure was reported in CNS tumor survivors following treatment with high dose alkylating agents but it does not seem to occur as a result of scatter radiation from cranio-spinal radiotherapy Male CCS treated with HSCT are generally able to retain normal Leydig cell function if they were conditioned for transplant using standard doses of 7, 72, 90, 94, cyclophosphamide or TBI if the cumulative testicular radiotherapy dose was < 20 Gy 121. Leydig-cell failure has also been reported in survivors of pediatric Hodgkin s Lymphoma 122 and of various solid tumors 76, 123 due to treatment with high dose alkylating agents and / or testicular exposure to radiotherapy. Diagnosis and Management Similarly to patients with LH/FSHD, patients with Leydig cell failure may experience pubertal delay, arrested puberty, or symptoms associated with low testosterone levels depending on the attained pubertal stage at the time of presentation. The diagnosis is suggested by AM 17

18 Page 18 of plasma testosterone levels that are below the normal range (adjusted to age) contrasting with elevated LH values 124, 125. The management is similar to guidelines available for the general population 79, 124. Male Germ Cell Failure (Oligo- and Azoospermia) Prevalence and Risk Factors Male germ cell failure with resulting infertility due to primary gonadal injury from alkylating agent chemotherapy or radiotherapy is among the most common complications reported in male CCS 81. The prevalence of male germ cell failure was reported at and 66.4% 89 in survivors tested with hormonal measurements (FSH and inhibin B) 3 and semen analysis 89 respectively. The risk is significant in all CCS exposed to alkylating agents or other gonadotoxic agents (Table 3) or any dose of radiotherapy to the testes even as low as 0.15 Gy 126. High risk groups include HSCT survivors conditioned with cyclophosphamide (especially at cumulative doses > 200 mg/kg) and busulfan or TBI , ALL survivors treated with alkylating agents at cyclophosphamide equivalent doses 4000 mg/m 2, or testicular radiotherapy 126, 131, 132, pediatric Hodgkin Lymphoma survivors treated with alkylating agents and / or infra- diaphragmatic radiotherapy 122, 133 and survivors of CNS 118, , 76, and other solid tumors with these treatment exposures. Data on the potential effects of targeted chemotherapy agents on male fertility are limited Diagnosis and Management The limited accuracy of indirect hormonal markers such as plasma levels of FSH and inhibin B mandates the performance of a semen analysis for the diagnosis of male germ cell failure 141. Whenever feasible, sperm banking should be offered to male patients prior to treatment with potentially gonadotoxic regimens

19 Page 19 of Primary Ovarian Insufficiency There is a strong interdependence between the viability of the oocyte and the integrity of the hormone producing granulosa cells in the ovarian follicle 142. The ovaries do not have the functional dichotomy with distinct endocrine /reproductive compartments as seen in the testes, and primary ovarian insufficiency (POI) is the generally accepted term to designate estrogen deficiency and expected fertility impairment due direct ovarian damage 142, 143. Prevalence and Risk Factors Ovarian function is vulnerable to gonadotoxic chemotherapy drugs such as alkylating agents (Table 3) and radiotherapy 80, 142, 143. Given the age-related natural decline of follicular reserve, older age at treatment exposure has also been described as an additional risk factor 142, 144. The prevalence of POI was reported at 11.8% among female CCS exposed to these high risk therapies 89. Survivors of CNS tumors may experience POI because of treatment with alkylating agents and ovarian exposure to radiation following cranio-spinal radiotherapy 119, 145. Up to 25.8% of females surviving medulloblastoma experienced POI; this is a likely underestimate given the young age (median age 16.6 years) of this cohort 87, 146. Patients treated with HSCT were reported to experience POI at even higher rates (84%) 147. The majority of female CCS conditioned for HSCT with cyclophosphamide and busulfan experience POI 94, 98. Reduced intensity conditioning regimens using melphalan seem to be less damaging to the ovaries, but long-term data are lacking 148. The risk of POI following TBI seems to primarily depend on age at exposure to radiotherapy: 50% of female CCS treated before the age of 10 years were reported to enter and complete puberty spontaneously while nearly all of those exposed after 10 years of age were diagnosed with POI Even with spontaneous puberty and/or normal progression of 19

20 Page 20 of development, premature menopause may still occur. Women having normal menstrual cycles and those able to become pregnant despite a past history of exposure to TBI experience high rates of miscarriage that have been attributed to adverse effects on the uterus and / or its blood supply 130, 152, 153. Female survivors of ALL treated with contemporary chemotherapy regimens have been reported to generally be able to experience normal pubertal development but longterm data on fertility are limited 154, 155. Female survivors of pediatric Hodgkin Lymphoma may experience POI because of treatment with alkylating agents and / or pelvic irradiation 122, 156 ; the risk increases with age at treatment 144 and may be lower in patients who had oophoropexy prior to radiotherapy 80 and those treated with chemotherapy alone 157. As with other CCS, female survivors of malignant extra-cranial solid tumors may experience POI because of the exposure to gonadotoxic chemotherapy or radiotherapy 29, 30, 32, 137, More recently, 131 I-MIBG for neuroblastoma was also reported to be a risk factor of POI 161. Data on fertility outcomes offtherapy and long-term for novel targeted chemotherapy agents are limited 8, 140. Diagnosis and Management Young pubertal CCS at risk of POI can be offered fertility preservation, preferably prior to cancer treatment, via mature oocyte cryopreservation, a technique that is no longer deemed experimental 142, 162. Depending on the attained pubertal stage at the time of cancer diagnosis, patients with POI may present with delayed puberty, interrupted puberty, primary or secondary amenorrhea, or premature menopause (i.e. before 40 years of age) 80, 146. Patients undergoing cancer treatments frequently experience interruptions in their pubertal development or amenorrhea; assessments of ovarian function are generally initiated if such dysfunctions last for more than 2 years after the completion of therapy 163. The laboratory diagnosis is primarily based on the observation of abnormally elevated FSH levels contrasting with low estradiol 20

21 Page 21 of concentrations 143. The role of other markers of follicular reserve such as antral follicle count via ultrasound and plasma anti-mullerian hormone levels has yet to be determined in CCS 143. Sex- hormone replacement is the mainstay of POI treatment; it aims at inducing pubertal development during childhood and adolescence and promoting skeletal, cardiovascular, psychological and sexual health during adulthood , 80,. It follows the same guidelines as in the general population 143. Information on screening and management is summarized in Table Decreased BMD Prevalence and Risk Factors The prevalence of decreased BMD in CCS was reported at 13-18% in long-term CCS 3. Up to 70% of children with leukemia present with disease-related skeletal abnormalities such as fractures and severe BMD deficit (BMD z-score -2) at the time of cancer diagnosis 164. Prolonged treatment with high dose glucocorticoids in children with ALL may also result in acute complications such as vertebral body compression fractures and avascular necrosis of the 461 bones 165, 166. Skeletal recovery was noted to begin shortly after the completion of ALL treatments, but BMD may remain abnormally low for age over several years depending on a variety of factors such as the severity of the deficit at baseline, the presence of other chronic health issues and lifestyle variables The prevalence of severe BMD deficit in HSCT survivors has been reported at 19-21% one to 5 years after the completion of therapy 168, 169. Patients treated with HSCT may experience decreased BMD because of the direct effect of leukemia on bone structure or because of treatments such as glucocorticoids and various medical complications related to transplant Additional risk factors include treatment with TBI 172 and /or prior exposure to CRT 177, young age at transplant 178, and a history of GHD 172 and / or 21

22 Page 22 of sex-hormone deficiency 173. Survivors of CNS tumors may experience decreased BMD because of treatment toxicity (glucocorticoids), and GH and / or sex-hormone deficiencies as well as sedentary lifestyle 179, 180. Changes in bone remodeling and secondary hyperparathyroidism have been recently described in patients treated with TKI 8. Diagnosis and Management Patients at risk of decreased BMD may be screened by using dual x-ray absorptiometry (DXA) upon entry to long-term follow-up and as clinically indicated thereafter 89. Interpretation of DXA may be confounded by pubertal delay or short stature 166. There are no specific management guidelines for low BMD in CCS; patients with hormonal deficiencies including vitamin D deficiency should be adequately treated and individuals should be educated on nutritional sources of calcium, the benefits of regular physical activity and the deleterious effects of smoking / alcohol consumption 181. Information on screening and management is summarized in Table Obesity and Diabetes Mellitus Prevalence and Risk Factors The risks of obesity (relative risk, 1.8; 95% CI, 1.7 to 2.0) and diabetes mellitus (relative risk, 1.9; 95% CI, 1.6 to 2.4) were significantly higher in survivors when compared to siblings in the CCSS cohort 16. High risk groups include CNS tumor survivors with a history of HP tumor or surgery; they may experience rapid weight gain and hypothalamic forms of obesity that are difficult to control 182, 183. The prevalence of obesity in patients with craniopharyngioma was reported at 55% despite the adequate replacement of all pituitary hormone deficiencies 183. Obesity also affects a substantial proportion of ALL survivors with a prevalence of 34-46% at 10 22

23 Page 23 of years of follow-up 184. While cranial irradiation represents a significant risk factor of obesity and diabetes mellitus in ALL survivors 185, those treated with chemotherapy alone continue to experience high rates of persistent obesity and overweight after many years of follow-up, likely because of their prolonged exposure to high dose glucocorticoids 186. Patients treated with HSCT do not seem to experience higher rates of obesity than similar aged individuals from the general population, but they were reported to have increased risks of insulin resistance, glucose intolerance and abnormal body composition 187. Diabetes mellitus was reported to affect 5% of HSCT recipients at a median 11 years after transplant 188. Insulin resistance was reported in as many as 52% of long-term HSCT survivors 189. Diabetes and insulin resistance do not seem to be related to obesity, as measured by BMI, in this population 190, 191 ; their pathophysiology seems to involve abnormal body fat distribution and possibly pancreatic islet cell injury due to TBI 192, 193. Survivors of solid tumors requiring treatment with abdominal radiotherapy may also have a higher risk of glucose intolerance and diabetes mellitus 76, Diagnosis and Management Screening every 6-12 months for overweight and obesity can be performed using weight, height and BMI measurements with subsequent testing for cardiovascular risk factors following the guidelines in place for the general population. Survivors treated with TBI need to be screened for diabetes mellitus using fasting blood glucose levels at least every two years regardless of whether they are obese or overweight 198. Management of obesity and diabetes mellitus in CCS follows similar steps as in the general population. Treatments of hypothalamic obesity have included octrerotide 199, diazoxide 200, 201, amphetamine derivatives 202 and more recently glucagonlike peptide 1 receptor agonists such as exenatide 203 ; data supporting the long-term efficacy and 23

24 Page 24 of safety of these medications are limited 204. Information on screening and management is summarized in Table Conclusion Endocrine complications are among the most prevalent late-effects in CCS. A systematic screening approach should facilitate the early diagnosis and treatment of these conditions and hopefully improve health outcomes. Endocrine late-effects may continue to appear years to decades after the completion of cancer treatments; the importance of long-term follow-up cannot be over-emphasized

25 Page 25 of Declaration of interest: Wassim Chemaitilly, MD has received consulting honoraria from Novo Nordisk and Pfizer. Laurie Cohen, MD has no potential conflicts to declare. Funding: Not applicable. Acknowledgements: None. 25

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37 Page 37 of Gurney JG, Kaste SC, Liu W, Srivastava DK, Chemaitilly W, Ness KK, Lanctot JQ, Ojha RP, Nottage KA, Wilson CL, Li Z, Robison LL & Hudson MM. Bone mineral density among long-term survivors of childhood acute lymphoblastic leukemia: results from the St. Jude Lifetime Cohort Study. Pediatr.Blood Cancer Petryk A, Bergemann TL, Polga KM, Ulrich KJ, Raatz SK, Brown DM, Robison LL & Baker KS. Prospective study of changes in bone mineral density and turnover in children after hematopoietic cell transplantation. J.Clin.Endocrinol.Metab Kaste SC, Shidler TJ, Tong X, Srivastava DK, Rochester R, Hudson MM, Shearer PD & Hale GA. Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation. Bone Marrow Transplant Dvorak CC, Gracia CR, Sanders JE, Cheng EY, Baker KS, Pulsipher MA & Petryk A. NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: endocrine challenges-thyroid dysfunction, growth impairment, bone health, & reproductive risks. Biol.Blood Marrow Transplant Bhatia S, Ramsay NK, Weisdorf D, Griffiths H & Robison LL. Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies. Bone Marrow Transplant Mostoufi-Moab S, Ginsberg JP, Bunin N, Zemel B, Shults J & Leonard MB. Bone density and structure in long-term survivors of pediatric allogeneic hematopoietic stem cell transplantation. J.Bone Miner.Res Aisenberg J, Hsieh K, Kalaitzoglou G, Whittam E, Heller G, Schneider R & Sklar C. Bone mineral density in young adult survivors of childhood cancer. J.Pediatr.Hematol.Oncol Nysom K, Holm K, Michaelsen KF, Hertz H, Jacobsen N, Muller J & Molgaard C. Bone mass after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplant Schimmer AD, Mah K, Bordeleau L, Cheung A, Ali V, Falconer M, Trus M & Keating A. Decreased bone mineral density is common after autologous blood or marrow transplantation. Bone Marrow Transplant Kerschan-Schindl K, Mitterbauer M, Fureder W, Kudlacek S, Grampp S, Bieglmayer C, Fialka- Moser V, Pietschmann P & Kalhs P. Bone metabolism in patients more than five years after bone marrow transplantation. Bone Marrow Transplant Gilsanz V, Carlson ME, Roe TF & Ortega JA. Osteoporosis after cranial irradiation for acute lymphoblastic leukemia. J.Pediatr Petryk A, Polgreen LE, Zhang L, Hodges JS, Dengel DR, Hoffmeister PA, Steinberger J & Baker KS. Bone mineral deficits in recipients of hematopoietic cell transplantation: the impact of young age at transplant. Bone Marrow Transplant Cohen LE, Gordon JH, Popovsky EY, Sainath NN, Feldman HA, Kieran MW & Gordon CM. Bone density in post-pubertal adolescent survivors of childhood brain tumors. Pediatr.Blood Cancer Gurney JG, Kadan-Lottick NS, Packer RJ, Neglia JP, Sklar CA, Punyko JA, Stovall M, Yasui Y, Nicholson HS, Wolden S, McNeil DE, Mertens AC & Robison LL. Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer Sala A & Barr RD. Osteopenia and cancer in children and adolescents: the fragility of success. Cancer Lustig RH, Post SR, Srivannaboon K, Rose SR, Danish RK, Burghen GA, Xiong X, Wu S & Merchant TE. Risk factors for the development of obesity in children surviving brain tumors. J.Clin.Endocrinol.Metab

38 Page 38 of Muller HL. Craniopharyngioma. Endocr.Rev Zhang FF, Kelly MJ, Saltzman E, Must A, Roberts SB & Parsons SK. Obesity in pediatric ALL survivors: a meta-analysis. Pediatrics e704-e Garmey EG, Liu Q, Sklar CA, Meacham LR, Mertens AC, Stovall MA, Yasui Y, Robison LL & Oeffinger KC. Longitudinal changes in obesity and body mass index among adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J.Clin.Oncol Zhang FF, Rodday AM, Kelly MJ, Must A, MacPherson C, Roberts SB, Saltzman E & Parsons SK. Predictors of being overweight or obese in survivors of pediatric acute lymphoblastic leukemia (ALL). Pediatr.Blood Cancer Armenian SH, Chemaitilly W, Chen M, Chow EJ, Duncan CN, Jones LW, Pulsipher MA, Remaley AT, Rovo A, Salooja N & Battiwalla M. National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Cardiovascular Disease and Associated Risk Factors Working Group Report. Biol Blood Marrow Transplant Hoffmeister PA, Storer BE & Sanders JE. Diabetes mellitus in long-term survivors of pediatric hematopoietic cell transplantation. J.Pediatr.Hematol.Oncol Taskinen M, Saarinen-Pihkala UM, Hovi L & Lipsanen-Nyman M. Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood. Lancet Chow EJ, Liu W, Srivastava K, Leisenring WM, Hayashi RJ, Sklar CA, Stovall M, Robison LL & Baker KS. Differential effects of radiotherapy on growth and endocrine function among acute leukemia survivors: a childhood cancer survivor study report. Pediatr.Blood Cancer Neville KA, Cohn RJ, Steinbeck KS, Johnston K & Walker JL. Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J.Clin.Endocrinol.Metab Wei C, Thyagiarajan M, Hunt L, Cox R, Bradley K, Elson R, Hamilton-Shield J, Stevens M & Crowne E. Reduced beta-cell reserve and pancreatic volume in survivors of childhood acute lymphoblastic leukaemia treated with bone marrow transplantation and total body irradiation. Clin.Endocrinol.(Oxf) Wei C, Thyagiarajan MS, Hunt LP, Shield JP, Stevens MC & Crowne EC. Reduced insulin sensitivity in childhood survivors of haematopoietic stem cell transplantation is associated with lipodystropic and sarcopenic phenotypes. Pediatr.Blood Cancer Cohen LE, Gordon JH, Popovsky EY, Gunawardene S, Duffey-Lind E, Lehmann LE & Diller LR. Late effects in children treated with intensive multimodal therapy for high-risk neuroblastoma: high incidence of endocrine and growth problems. Bone Marrow Transplant Meacham LR, Sklar CA, Li S, Liu Q, Gimpel N, Yasui Y, Whitton JA, Stovall M, Robison LL & Oeffinger KC. Diabetes mellitus in long-term survivors of childhood cancer. Increased risk associated with radiation therapy: a report for the childhood cancer survivor study. Arch.Intern.Med van WM, Neggers SJ, Raat H, van Rij CM, Pieters R & MM vdh-e. Abdominal radiotherapy: a major determinant of metabolic syndrome in nephroblastoma and neuroblastoma survivors. PLoS.One e de Vathaire F, El-Fayech C, Ben Ayed FF, Haddy N, Guibout C, Winter D, Thomas-Teinturier C, Veres C, Jackson A, Pacquement H, Schlumberger M, Hawkins M, Diallo I & Oberlin O. Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol Baker KS, Chow E & Steinberger J. Metabolic syndrome and cardiovascular risk in survivors after hematopoietic cell transplantation. Bone Marrow Transplant

39 Page 39 of Lustig RH, Hinds PS, Ringwald-Smith K, Christensen RK, Kaste SC, Schreiber RE, Rai SN, Lensing SY, Wu S & Xiong X. Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial. J.Clin.Endocrinol.Metab Brauner R, Serreau R, Souberbielle JC, Pouillot M, Grouazel S, Recasens C, Zerah M, Sainte-Rose C & Treluyer JM. Diazoxide in Children With Obesity After Hypothalamic-Pituitary Lesions: A Randomized, Placebo-Controlled Trial. J Clin Endocrinol Metab Hamilton JK, Conwell LS, Syme C, Ahmet A, Jeffery A & Daneman D. Hypothalamic Obesity following Craniopharyngioma Surgery: Results of a Pilot Trial of Combined Diazoxide and Metformin Therapy. Int J Pediatr Endocrinol Mason PW, Krawiecki N & Meacham LR. The use of dextroamphetamine to treat obesity and hyperphagia in children treated for craniopharyngioma. Arch.Pediatr.Adolesc.Med Lomenick JP, Buchowski MS & Shoemaker AH. A 52-week pilot study of the effects of exenatide on body weight in patients with hypothalamic obesity. Obesity (Silver Spring) Cohen LE. Update on childhood craniopharyngiomas. Curr Opin Endocrinol Diabetes Obes Legends to Tables and Figures 1168 Table 1: Risk Factors and Management Guidelines of Endocrine Late Effects: Central / Hypothalamic-Pituitary 1169 Disorders 1170 Table 2: Risk Factors and Management Guidelines of Endocrine Late Effects: Common Primary Disorders 1171 Table 3: Chemotherapy Agents Associated with Gonadal Toxicity 1172 Figure 1: Relative Proportions and Overlap among Anterior Pituitary Deficiencies following Cranial 1173 Radiotherapy

40 Proportions and overlap among anterior pituitary deficiencies following cranial radiotherapy. Page 40 of 43 Wassim Chemaitilly et al. JCO 2015;33: by American Society of Clinical Oncology